The immediate goal of this research is to contribute basic knowledge of mechanisms that enable the closely-linked genes for hemoglobin synthesis in the mouse to be expressed sequentially and differentially between embryonic and adult life. Chemical studies are to be done on abnormal hemoglobins of mice previously induced by X-rays and to use the data to explain why the relative amounts of non-alpha-chains are different in hemoglobins of alpha-thalassemic and normal mice. Of the three independent cases of alpha-thalassemia trait produced in (101 X SEC)F1 progeny of irradiated SEC males, two were fertile and these mutations are being placed on both SEC and C57BL backgrounds. The expression of the mutations with respect to clinical and pathological indices from fertilization of the egg until death are being studied. When the mutants are sufficiently inbred, experiments are planned to determine whether transplanted bone marrow cells from normal mice have the ability to outgrow, and thus replace naturally, the genetically defective bone marrow cells of alpha-thalassemic mice. Several thousand (SEC X CBA)F1 progeny of irradiated CBA males will be raised and screened for structural and/or deficiency mutations at the hemoglobin loci, with a special interest of producing mouse models of beta-chain hemoglobinopathies of man. Such models will be used to study methods for the transfer and activation of normal hemoglobin genes into genetically defective stem cells of hematopoietic tissues.